Collagen Undergoes Extensive Posttranslational Modifications

Newly synthesized collagen undergoes extensive post-translational modification before becoming part of a mature extracellular collagen fiber (Table 48-3). Like most secreted proteins, collagen is synthesized on ribo-somes in a precursor form, preprocollagen, which contains a leader or signal sequence that directs the polypeptide chain into the lumen of the endoplasmic reticulum. As it enters the endoplasmic reticulum, this leader sequence is enzymatically removed. Hydroxyla-tion of proline and lysine residues and glycosylation of hydroxylysines in the procollagen molecule also take place at this site. The procollagen molecule contains

Table 48-3. Order and location of processing of the fibrillar collagen precursor.


1. Cleavage of signal peptide

2. Hydroxylation of prolyl residues and some lysyl residues; glycosylation of some hydroxylysyl residues

3. Formation of intrachain and interchain S-S bonds in extension peptides

4. Formation of triple helix Extracellular

1. Cleavage of amino and carboxyl terminal propeptides

2. Assembly of collagen fibers in quarter-staggered alignment

3. Oxidative deamination of £-amino groups of lysyl and hydroxylysyl residues to aldehydes

4. Formation of intra- and interchain cross-links via Schiff bases and aldol condensation products polypeptide extensions (extension peptides) of 20-35 kDa at both its amino and carboxyl terminal ends, neither of which is present in mature collagen. Both extension peptides contain cysteine residues. While the amino terminal propeptide forms only intrachain disul-fide bonds, the carboxyl terminal propeptides form both intrachain and interchain disulfide bonds. Formation of these disulfide bonds assists in the registration of the three collagen molecules to form the triple helix, winding from the carboxyl terminal end. After formation of the triple helix, no further hydroxylation of proline or lysine or glycosylation of hydroxylysines can take place. Self-assembly is a cardinal principle in the biosynthesis of collagen.

Following secretion from the cell by way of the Golgi apparatus, extracellular enzymes called procollagen aminoproteinase and procollagen carboxypro-teinase remove the extension peptides at the amino and carboxyl terminal ends, respectively. Cleavage of these propeptides may occur within crypts or folds in the cell membrane. Once the propeptides are removed, the triple helical collagen molecules, containing approximately 1000 amino acids per chain, spontaneously assemble into collagen fibers. These are further stabilized by the formation of inter- and intrachain cross-links through the action of lysyl oxidase, as described previously.

The same cells that secrete collagen also secrete fi-bronectin, a large glycoprotein present on cell surfaces, in the extracellular matrix, and in blood (see below). Fi-bronectin binds to aggregating precollagen fibers and alters the kinetics of fiber formation in the pericellular matrix. Associated with fibronectin and procollagen in this matrix are the proteoglycans heparan sulfate and chondroitin sulfate (see below). In fact, type IX collagen, a minor collagen type from cartilage, contains attached proteoglycan chains. Such interactions may serve to regulate the formation of collagen fibers and to determine their orientation in tissues.

Once formed, collagen is relatively metabolically stable. However, its breakdown is increased during starvation and various inflammatory states. Excessive production of collagen occurs in a number of conditions, eg, hepatic cirrhosis.

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